Hyperlipidemia is the primary cause for cardiovascular disease (CVD) and other peripheral vascular diseases. High risk of CVD is related to the higher LDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) seen in hyperlipidemia. Patients having glucose intolerance/insulin resistance in addition to hyperlipidemia have higher risk of CVD. Numerous studies in the past have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and VLDL and increasing HDL (High Density Lipoprotein) cholesterol help in preventing cardiovascular diseases.
Diabetes is a disease, which severely affects the quality of life of a large population. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises resulting in frank diabetes. Among developed countries, diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75 : 809-817; N. Engl. J. Med. (1987) 317 : 350-357; J. Clin. Endocrinol. Metab., (1988) 66: 580-583; J. Clin. Invest., (1975) 68 : 957-969) and renal complications (See Patent Application No. WO 95/21608). It is increasingly being recognized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link-Syndrome-X.
Thus, therapeutic agents which improve insulin resistance, lower plasma triglycerides, total cholesterol, LDL and VLDL and increase HDL will have great significance in preventing cardiovascular morbidity and improving quality of life.
Peroxisome proliferator activated receptors (PPAR) are members of the nuclear receptor super family. The gamma (.gamma.) isoform of PPAR (PPAR.gamma.) has been implicated in regulating differentiation of adipocytes (Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell, (1995) 83: 803-812), whereas the alpha (.alpha.) isoform of PPAR (PPAR.alpha.) mediates fatty acid oxidation (Trend. Endocrin. Metab., (1993) 4: 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol. (1995) 5: 618-621). PPAR.alpha. agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that there exists synergism for the molecules, which are agonists for both PPAR.alpha. and PPAR.gamma. and suggested to be useful for the treatment of syndrome X (WO 97/25042). Similar synergism between the insulin sensitizer (PPAR.gamma. agonist) and HMG CoA reductase inhibitor has been observed which may be useful for the treatment of atherosclerosis and xanthoma. (EP 0 753 298).
A few .beta.-aryl-.alpha.-hydroxy propionic acids, their derivatives and their analogs have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia. Some of such compounds described in the prior art are outlined below:
i) U.S. Pat. No. 5,306,726; WO91/19702 disclose several 3-aryl-2-hydroxypropionic acid derivatives of general formulas (IIa) and (IIb) as hypolipidemic and hypoglycemic agents. ##STR3##
Examples of these compounds are shown in formulas (II c) and (II d) ##STR4##
ii) International Patent Applications, WO 95/03038 and WO 96/04260 disclose compounds of formula (II e) ##STR5## wherein R.sup.a represents 2-benzoxazolyl or 2-pyridyl and R.sup.b represents CF.sub.3, CH.sub.2 OCH.sub.3 or CH.sub.3. A typical example is (S)-3-[4-[2-[N-(2-benzoxazolyl]N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifl uoroethoxy)propanoic acid (II f). ##STR6##
iii) International Patent Application Nos. WO 94/13650, WO 94/01420 and WO 95/17394 disclose the compounds of general formula (II g) EQU A.sup.1 --X--(CH.sub.2).sub.n --O--A.sup.2 --A.sup.3 --Y.R.sup.2(II g)
wherein A.sup.1 represents aromatic heterocycle, A.sup.2 represents substituted benzene ring and A.sup.3 represents moiety of formula (CH.sub.2).sub.m --CH--(OR.sup.1) wherein R.sup.1 represents alkyl groups, m is an integer; X represents substituted or unsubstituted N; Y represents C.dbd.O or C.dbd.S. R.sup.2 represents OR.sup.3 where R.sup.3 may be alkyl, aralkyl, or aryl group. An example of these compounds is shown in formula (II h) ##STR7##